Project Summary (Abstract): The elderly are highly susceptible to a variety of virus infections. In particular, virus infections of the respiratory tract account for a substantial increase in morbidity and mortality in the aged individuals. Impaired innate and adaptive antiviral responses are, in part, responsible for increased disease severity in the elderly. Interferon (IFN) cytokines, specifically, type I IFN [IFN-ab] and type III IFNs [IFN-lambda (1-3, l)], constitute the first line of innate defense against virus infections. While IFN-ab response is protective, an excessive IFN-ab response may cause immunopathology and severe disease. In contrast, IFN-l is a non-redundant frontline antiviral cytokine that acts specifically on airway epithelial cells without causing excessive inflammation. Pathogenic human coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) cause severe disease in the elderly. Similarly, mouse adapted strains of SARS-CoV and mouse hepatitis virus- 1 (MHV-1, a pneumotropic mouse CoV) cause age-dependent increases in disease severity. Our preliminary results show that: a) IFN-l and interferon stimulated gene (ISG) expression is significantly reduced in the lungs of CoV-infected aged mice, and b) early therapeutic administration of IFN-l provides complete protection against lethal CoV infection in susceptible mice. In this project, we will characterize IFN-l and ISG responses, identify the source and investigate the mechanistic basis for impaired IFN-l and ISG response in SARS-CoV infected aged mice. Additionally, we will examine the role of IFN-l in host protection during aging, and test the prophylactic and therapeutic efficacy of recombinant-IFN-l (rIFN-l) in young (2 months) and aged (18-20 months) mice following intranasal infection with SARS-CoV. To address these goals, we will use immunology-, virology- and molecular biology-based in vitro and in vivo experiments. In vivo studies will include use of IFN-ab receptor (IFNAR) and IFN-l receptor (IFNLR) blocking antibodies and of WT, IFNAR-/- and IFNLR -/- mice. Our goal is to establish IFN-l as a potential therapeutic agent for treating respiratory virus infections in the elderly. Since CoVs induce age-dependent respiratory illness both in humans and in mice, we believe that aged mice infected with CoV are an ideal platform for studying the immunobiology of respiratory virus infections in the elderly. The results obtained from this study will provide a foundation for testing therapeutic potential of rIFN-l in CoV and other respiratory virus infections.